3 CME REVIEW ARTICLE

Volume 74, Number 1

OBSTETRICAL AND GYNECOLOGICAL SURVEY
Copyright © 2019 Wolters Kluwer Health,
Inc. All rights reserved.

CHIEF EDITOR'S NOTE: This article is part of a series of continuing education activities in this Journal through which a total of
36 AMA PRA Category 1 Credits™ can be earned in 2019. Instructions for how CME credits can be earned appear on the last
page of the Table of Contents.

Tocolysis: A Review of the Literature

Margaret Hanley, BA,* Lauren Sayres, MD,† Emily S. Reiff, MD,‡
Amber Wood, MD,‡ Chad A. Grotegut, MD, MPH,§ and Jeffrey A. Kuller, MD¶
*Premedical Student, †Resident, ‡Maternal-Fetal Medicine Fellow, §Associate Professor, and ¶Professor, Division of Maternal
Fetal Medicine, Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC
Downloaded from http://journals.lww.com/obgynsurvey by BhDMf5ePHKbH4TTImqenVPdd2D9XRrfdTQPymzVNMpii1vmm8Dxua3HnluF3ZCXy on 01/13/2019

Importance: Preterm delivery represents an important cause of infant morbidity and mortality. Various
tocolytics have been studied with the objective of stopping preterm labor, increasing gestational age at de-
livery, and preventing complications related to preterm birth.
Objective: This review aims to summarize the major classes of tocolytics and review the evidence regarding
use of each.
Evidence Acquisition: A PubMed search of the following terms was performed to gather relevant data: “tocolytic,”
“preterm labor,” “preterm delivery,” “PPROM,” “magnesium,” “indomethacin,” “nifedipine,” and “betamimetics.”
Results: The benefits and risks of nonsteroid anti-inflammatory drugs, calcium channel blockers, magnesium,
and betamimetics are reviewed. Calcium channel blockers afford superior outcomes in terms of prolonging ges-
tation and decreasing neonatal morbidity and mortality with the fewest adverse effects.
Conclusions and Relevance: Tocolytics, particularly calcium channel blockers, may provide benefit to preg-
nant women and their infants. Their use should be tailored to the particular clinical circumstances of the patient
and used in conjunction with other management strategies (e.g., administration of corticosteroids for fetal lung
maturation or magnesium for neuroprotection and transfer to a tertiary medical center). Further research and pro-
fessional guidelines are needed on optimal use of these agents.
Target Audience: Obstetricians and gynecologists, family physicians.
Learning Objectives: After participating in this activity, the provider should be better able to compare the
major classes of tocolytics, including mechanisms of action; distinguish the role tocolytics play in preterm la-
bor and appropriate clinical indication and course; and choose a tocolytic based on evidence regarding the
potential benefits and risks.

Preterm delivery, defined as birth between 20 0/7 and
36 6/7 weeks' gestation, is the leading cause of neonatal
mortality.1 Approximately 70% of neonatal deaths and
36% of infant deaths, as well as 25% to 50% of cases of
long-term neurological impairments in children, can
be attributed to prematurity.2 Preterm labor is the
most common reason for antenatal hospitalization.3
Preterm contractions, however, may not result in pre-
term birth. Approximately 30% of preterm contractions
All authors, faculty, and staff in a position to control the content of
this CME activity and their spouses/life partners (if any) have disclosed
that they have no financial relationships with, or financial interests in,
any commercial organizations relevant to this educational activity.
Correspondence requests to: Emily S. Reiff, MD, 2608 Erwin Rd,
Suite 210, Durham, NC 27705. E-mail: emily.reiff@duke.edu.
www.obgynsurvey.com | 50
resolve spontaneously, and 50% of women hospitalized
for preterm labor ultimately deliver at term.4,5 Identifica-
tion of women who present with preterm contractions
who will eventually deliver preterm represents an impor-
tant challenge for obstetricians to appropriately manage
these women.
Uterine contractions are the most recognizable sign of
preterm birth. Inhibiting contractions, therefore, has been
the focus of treatment for preterm labor. Historically,
methods to suppress preterm contractions have included
bed rest, abstinence from intercourse, alcohol, and hy-
dration. The effectiveness of these interventions is lack-
ing in evidence.6 Moreover, adverse effects have been
reported; bed rest, in particular, has a demonstrated as-
sociation with an increased risk of venous thromboembo-
lism, increased concentration of bone resorption markers,

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 Tocolysis: A Review of the Literature • CME Review Article
deconditioning, and depression.7–9 Alcohol, specifically
ethanol, is ineffective compared with a placebo, and its
use has been stopped due to safety concerns for mother
and her baby, including neurodevelopmental status.10
Modern treatment of preterm labor includes the use of
tocolytic drugs to inhibit contractions. The American
College of Obstetricians and Gynecologists (ACOG)
supports tocolytic therapy to effect short-term (up to
48 hours) prolongation of pregnancy and allow for the
administration of corticosteroids.11 This treatment is
supported by ACOG in the absence of contraindication
to tocolysis.11 Maintenance therapy with tocolytics is not
recommended, and level A evidence suggests that con-
tinuation of tocolysis beyond 48 hours' duration does
not improve preterm birth rates or neonatal outcomes.11
The ACOG recommends nonsteroid anti-inflammatory
drugs (NSAIDs), calcium channel blockers (CCBs), or
beta-adrenergic receptor agonists (betamimetics) as
first-line tocolytics; magnesium sulfate has also been
historically utilized for tocolysis. Each has a unique
mechanism of action and risk-benefit profile. This re-
view aggregates research on the efficacy, neonatal out-
comes, and potential adverse outcomes for each class
of tocolytic drugs.
NONSTEROID
ANTI-INFLAMMATORY DRUGS
By inhibiting the activity of cyclooxygenase enzymes,
COX1 and/or COX2, NSAIDs decrease prostaglandin
production, which in turn downregulates uterine contrac-
tility. Indomethacin is an NSAID commonly used for
tocolytic treatment and is the most studied of NSAIDs
for tocolysis.
Multiple studies have compared the administration of
indomethacin with placebo for tocolysis. Overall, com-
pared with placebo, indomethacin appears to prolong
pregnancy but does not result in measurable differences
in neonatal morbidity or mortality.12 A 1980 study com-
pared indomethacin to placebo with treatment failure
defined as progression beyond 4 cm cervical dilation af-
ter 24 hours of treatment.13 The study reported treatment
failure in 1 of 15 women treated with indomethacin
and 9 of 15 women receiving placebo.13 In 1999, a
study of 34 women demonstrated that pregnancy
was prolonged by more than 48 hours for 81% of
women treated with a 48-hour course of indomethacin
versus 56% of women in the placebo group.14 There
was no difference in perinatal mortality and severe
neonatal morbidity, as defined by necrotizing entero-
colitis, bronchopulmonary dysplasia, intraventricular
hemorrhage, or periventricular leukomalacia, between
treatment and placebo groups.14 In a small study of
Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
51
36 women, indomethacin resulted in a 83.3% reduction
in preterm birth before 37 weeks compared with a
22.2% decrease in the placebo group.12,15 Taken to-
gether, these studies suggest a significant prolonga-
tion of pregnancy with the use of indomethacin, but
no improvement in neonatal outcomes for women with
premature labor.
In a 1991 study of 60 women, preterm labor was
arrested after 48 hours for 96% of subjects receiving
NSAIDs compared with 76% of subjects receiving
betamimetics.16 Compared with betamimetics, use of
NSAIDs resulted in a relative risk of 0.27 (95% confident
interval [CI], 0.08–0.96) for preterm birth within 48 hours
and a relative risk of 0.53 (95% CI, 0.28–0.99) for pre-
term birth before 37 weeks.12 This study, in consideration
with an additional 19 studies, also informed the 2015
Cochrane review finding that NSAIDs, as compared with
betamimetics, afforded fewer adverse maternal adverse
effects, and decreased rates of early cessation of therapy.12
There was no difference in neonatal morbidity or mortal-
ity with NSAIDs as compared with betamimetics.12
There are reported neonatal risks associated with
NSAID administration for tocolysis, including platelet
dysfunction, deleterious effects on gastrointestinal
oxygen consumption, and altered intestinal, cerebral,
and renal blood flow ultimately resulting in increased
risk of premature closure of the ductus arteriosus and
oligohydramnios.17–19 Ductal constriction is most
likely to occur when indomethacin is administered at
gestational ages greater than 32 weeks.17,18 In several
studies, effects appear to be reversible with cessation
of NSAID treatment, although the risk increases after
48 hours of administration.18,20 There is some evi-
dence that indomethacin administered before 30 weeks'
gestation may also increase the risk of other neonatal
sequelae, including necrotizing enterocolitis and intra-
ventricular hemorrhage17; however, these studies are
limited by possible confounders such as the use of a
first-line tocolytic before administration of indometha-
cin.20 Nonetheless, a 1997 study found that the benefits
of delayed delivery from administering indomethacin
outweighed potential neonatal risks before 32 weeks'
gestation.21
In conclusion, there may be some benefit of NSAIDs
for prolongation of pregnancy; however, importantly,
this benefit has not translated into improved neonatal
outcomes. When compared with betamimetics or pla-
cebo, NSAIDs are associated with a reduction in pre-
term birth before 37 weeks and a reduction in birth
rates within 48 hours. When compared with other mo-
dalities, indomethacin is associated with fewer adverse
maternal effects and adverse effects requiring cessation.
Indomethacin has been associated with closure of the
52 Obstetrical and Gynecological Survey
ductus arteriosus and oligohydramnios; some studies
have also demonstrated an increased risk of necrotizing
enterocolitis and intraventricular hemorrhage, particu-
larly when used as antenatal therapy in neonates born
at or before 30 weeks' gestation.22
CALCIUM CHANNEL BLOCKERS
Calcium channel blockers act as tocolytics by
inhibiting calcium flow through cell membranes and
inhibiting the release of intracellular calcium ions
from the sarcoplasmic reticulum. This action pre-
vents calcium-dependent myosin light-chain kinase-
mediated phosphorylation, resulting in myometrial
relaxation. In particular, nifedipine is the most com-
monly used CCB for tocolysis.
A Cochrane review of 38 trials of CCBs involving
3550 women was published in 2014. When compared
with placebos, administration of CCBs resulted in a
relative risk of 0.30 (95% CI, 0.21–0.43) for preterm
birth within 48 hours.23 When compared with other
tocolytics (including betamimetics, NSAIDs, and mag-
nesium), there were no observed differences in birth
rate within 48 hours, perinatal mortality, or serious ma-
ternal outcome defined as death, cardiac or respiratory
arrest, or admission to intensive care unit.24 When com-
pared with betamimetics, CCBs resulted in an average
additional delay to delivery of 4.4 days and fewer
maternal adverse effects, such as hypotension and
tachycardia.23 When compared with magnesium,
CCBs resulted in decreased maternal adverse effects
and decreased duration of neonatal intensive care
unit stay.23
A 2011, systematic review compared outcomes of
nifedipine versus betamimetics across 16 studies. The
authors concluded that nifedipine was superior to
betamimetics in arresting birth within 48 hours and
7 days of treatment and before 34 weeks' gestation.23
Nifedipine also resulted in decreased neonatal adverse
outcomes relative to both betamimetics and NSAIDs
as well as decreased maternal adverse effects compared
with both betamimetics and magnesium.23
In conclusion, CCBs appear to have benefits over pla-
cebo in prolongation of pregnancy beyond 48 hours.
When compared with betamimetics, CCBs were more
beneficial in prolonging pregnancy while lowering neo-
natal morbidity and reducing maternal adverse adverse
effects. When compared with magnesium, CCBs had
fewer maternal adverse effects. When compared with
NSAIDs, CCBs had improved neonatal morbidity.
Caution should be used when using nifedipine and
magnesium in combination as described later.
Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
MAGNESIUM SULFATE
Administration of magnesium sulfate inhibits myosin
light-chain kinase activity by competing with intracellular
calcium, leading to decreased myometrial contractility.25
A 2014 Cochrane review included 37 trials of 3571
women comparing magnesium sulfate to other tocolytics
and placebo.26 The review found that women who re-
ceived magnesium sulfate were as likely to give birth
within 48 hours as women who did not receive mag-
nesium sulfate (whether they received no treatment,
placebo, or other tocolytic treatments including
betamimetics, CCBs, and NSAIDs).26 Similarly, ad-
ministration of magnesium sulfate resulted in no dif-
ference in the risk of preterm birth within 48 hours
and no difference in serious neonatal outcomes.26 More-
over, when compared with placebo or no treatment, ad-
ministration of magnesium sulfate resulted in a possible
increased risk of neonatal death (relative ratio, 4.56;
95% CI, 1.00–20.86, 2 trials of 287 infants).26 Ten trials
of 991 infants comparing magnesium sulfate to other
tocolytics did not show this outcome.26
A 2009 review of 19 randomized controlled trials
found that magnesium sulfate did not decrease the fre-
quency of birth within 48 hours or 7 days when com-
pared with placebo or no tocolytic treatment.27 In
addition, there was no reduction in preterm birth be-
fore 37 weeks.27 No single study in this review dem-
onstrated improvement in preterm delivery rates with
magnesium sulfate.27
In conclusion, magnesium sulfate does not appear to
be effective at preventing preterm birth and should not
be used as a tocolytic agent.
Calcium Channel Blockers With Magnesium
Coadministration of magnesium and nifedipine can
potentially interact leading to hypotension, neuromus-
cular blockade, and/or cardiovascular collapse. These
effects are described in several case reports. A retro-
spective cohort study from 2004, however, found no
increased risk of serious maternal adverse events in
women with severe preeclampsia who received con-
temporaneous magnesium and nifedipine.28 Regard-
less, ACOG recommends caution when using CCBs
in combination with magnesium sulfate because of
these potential serious maternal complications.11
BETA-ADRENERGIC
RECEPTOR AGONISTS
Betamimetics bind to beta2 adrenergic receptors, which
decreases myometrial contractility through a cAMP-
protein kinase-myosin light-chain kinase pathway.25
 Tocolysis: A Review of the Literature • CME Review Article
The betamimetic agent most commonly used for
tocolysis is terbutaline.
A 2014 Cochrane review of 20 trials compared ad-
ministration of betamimetics to placebo.29 Analysis of
1209 women demonstrated a relative risk of preterm
birth within 48 hours with betamimetics of 0.68 (95%
CI, 0.53–0.88), although the overall preterm birth risk
was equivalent between betamimetics and placebo.29
There was no difference in neonatal outcomes as de-
fined by perinatal deaths within 7 days, respiratory
distress syndrome, or cerebral palsy.29 This review
also highlighted adverse maternal adverse effects of
betamimetics, particularly consequences of withdrawal,
including chest pain, palpitations, tremor, headaches,
cardiotoxicity, and death.29
In conclusion, betamimetics may delay birth, allowing
for patient transfer and for completion of steroid courses,
but have a high rate of maternal adverse effects.
Betamimetics should not be used for prolonged tocolysis,
beyond 48 hours, due to the risk of serious maternal car-
diac toxicity or even death. The US Food and Drug Ad-
ministration has issued a black box warning for these
drugs due to this risk.30 Therefore, alternative agents
should be recommended when choosing a tocolytic.
Choosing a Tocolytic
Several studies have compared multiple classes of
tocolytics. A systematic review from 2012 included
95 randomized controlled trials of women in preterm
labor.31 Compared with placebo, the probability of
delaying delivery by 48 hours was highest with NSAIDs,
followed by magnesium, CCBs, and betamimetics.31
The likelihood of maternal adverse effects that required
a change in treatment was greater with betamimetics,
magnesium, and CCBs than with NSAIDs.31 Taking
into account the outcomes of 48-hour delay in delivery,
respiratory distress syndrome, neonatal mortality, and
maternal adverse effects, NSAIDs and CCBs exhibited
the best probability of being ranked as one of the top 3
most efficacious agents.31
On the other hand, a 2014 randomized study of 301
women in preterm labor at 24 to 32 weeks' gestation
compared outcomes of those receiving magnesium,
indomethacin or nifedipine.32 Gestational age at de-
livery and interval to delivery were similar among the
3 groups.32 Composite neonatal morbidity and mortal-
ity did not differ among the groups.32
This finding is also supported by a 2015 retrospective
cohort study of women admitted in preterm labor be-
tween 23 and 32 weeks.33 Women who received any
tocolytic were significantly more likely to be pregnant
at least 48 hours after admission. The proportions of
Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
53
women who delivered within 7 days and their gesta-
tional age at delivery, as well as initial neonatal out-
comes and composite severe neonatal morbidity, were
similar across tocolytic treatments.33
A 2016 secondary analysis of a randomized controlled
trial evaluated treatment with indomethacin, magnesium,
and nifedipine in women with advanced cervical dilation
(4 to 6 centimeters).34 The percent of women who re-
mained undelivered at 48 hours, 72 hours, and 7 days,
as well as gestational age at delivery, were similar
among the tocolytic classes.34 When stratified by
tocolytic treatment, no differences in neonatal out-
comes were observed.34
When comparing multiple tocolytics, NSAIDs and
CCBs had the highest probability of delaying delivery.
There is evidence that NSAIDs and CCBs are superior
to magnesium or betamimetics in terms of improving
neonatal and maternal outcomes and decreasing ma-
ternal adverse effects. Therefore, it is recommended
that CCBs be used at and after 32 weeks' gestation
to avoid premature closure of the ductus arteriosus as-
sociated with NSAID use and that either nifedipine or
NSAIDs be used between viability and 32 weeks to al-
low for betamethasone administration for fetal lung
maturity (see Table 1 for contraindications to use of
various tocolytics).
Special Consideration: Use of Tocolytics in Preterm
Premature Rupture of Membranes
The use of tocolysis in Preterm Premature Rupture of
Membranes (PPROM) is controversial, with practice
patterns varying among maternal-fetal medicine spe-
cialists.35,36 In a survey of 827 Society for Maternal-
Fetal Medicine members, 32% reported that they would
recommend tocolysis to women with PPROM with
contractions and 29% would recommend tocolysis to
women with PPROM without contractions.37 In a re-
cent Cochrane review, the authors reviewed 8 studies
(n = 408) of women with PPROM who did or did
not receive tocolytic treatment.37 Administration of
TABLE 1
Contraindications to Tocolytic Use
Tocolytic Absolute or Relative Contraindications
NSAIDs Renal dysfunction, peptic ulcer disease,
thrombocytopenia, bleeding disorder
CCBs Hypotension, preload-dependent cardiac disease,
coadministration of magnesium
Magnesium Myasthenia gravis, renal dysfunction, heart block,
coadministration of CCBs
Betamimetics Poorly controlled diabetes, hyperthyroidism,
arrhythmia, heart failure
54 Obstetrical and Gynecological Survey
tocolytics was found to be associated with longer la-
tency (between PPROM and delivery) and fewer births
within 48 hours. Although there was no significant dif-
ference in perinatal mortality, an association between
an increased risk of adverse neonatal effects and the ad-
ministration of tocolytics was, in fact, observed.38 Neo-
nates whose mothers received tocolytics after PPROM
had an increased risk of an Apgar score less than 7 at
5 minutes and an increased need for neonatal ventila-
tion.38 Borderline significance (P = 0.051) between
tocolytic administration and chorioamnionitis was noted,
with a subanalysis attributing this greater risk of chorio-
amnionitis to betamimetic administration. ACOG states
that “there are insufficient data to support or refute the
use of prophylactic tocolysis in the setting of preterm
PROM…in the setting of active ruptured membranes
with active labor, therapeutic tocolysis has not been
shown to prolong latency or improve neonatal outcomes.
Therefore, therapeutic tocolysis is not recommended.”38
DISCUSSION
According to ACOG guidelines, a short course of
tocolytics should be administered in patients with pre-
term labor (in the absence of contraindications) to allow
for the administration of corticosteroids for fetal lung
maturation, use of magnesium for neuroprotection,
and/or transfer to a tertiary facility. Systematic reviews
and meta-analyses demonstrate that certain tocolytics,
particularly NSAIDs and CCBs, can delay delivery in
the setting of preterm labor and afford neonatal benefits
with few potential untoward effects.39,40 Betamimetics
may offer a modest benefit in delaying delivery, but carry
the potential for serious deleterious consequences. Mag-
nesium does not appear to be of benefit for tocolysis.
Tocolytics have no proven benefit in the setting of
PPROM and thus are not recommended by ACOG.
Limitations of the data available to date include small
sample sizes, resultant limitations in the evaluation of
rare outcomes, variable dosing of tocolytics, and perfor-
mance of studies before the routine use of corticosteroids
for fetal lung maturity and/or antibiotic use specific to
PPROM to increase the latency period. Moreover, the
outcome variables of these studies are inconsistent,
ranging from a specific time delay to delivery, preterm
delivery rate (defined either as delivery before 34 or
37 weeks), neonatal morbidity (sometimes qualified
only to include serious outcomes) or mortality, or ma-
ternal adverse effects. Ideally, future trials will incorporate
a large number of women, will standardize tocolytic
regimens as well as adjunctive management strategies
including steroid and magnesium use, and will evaluate
clinical sequelae for mothers and infants over a
Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
prolonged period. Furthermore, it would be advanta-
geous to stratify women in preterm labor by gestational
age, cervical dilation at onset of treatment, and PPROM
status to optimize potential benefits of tocolysis.
CONCLUSIONS
Tocolysis, particularly with NSAIDs and CCBs, rep-
resents an important modality for managing preterm la-
bor. Discretion is required to balance the potential
benefits and risks of a given tocolytic drug for a partic-
ular woman's clinical circumstances. More research is
required to understand the best scenario for administra-
tion of these drugs and will ideally allow for the produc-
tion of comprehensive professional guidelines, including
a clear decision-making pathway, for tocolysis for pre-
term labor and PPROM.
REFERENCES
1. Goldenberg RL, Culhane JF, Iams JD, et al. Epidemiology and
causes of preterm birth. Lancet. 2008;371:75–84.
2. Mathews TJ, MacDorman MF. Infant mortality statistics from the
2006 period linked birth/infant death data set. Natl Vital Stat Rep.
2010;58:1–31.
3. Rundell K, Panchal B. Preterm labor: prevention and manage-
ment. Am Fam Physician. 2017;95:366–372.
4. King JF, Grant A, Keirse MJ, et al. Beta-mimetics in preterm la-
bour: an overview of the randomized controlled trials. Br J Obstet
Gynaecol. 1988;95:211–222.
5. McPheeters ML, Miller WC, Hartmann KE, et al. The epidemiology
of threatened preterm labor: a prospective cohort study. Am J
Obstet Gynecol. 2005;192:1325–1329. discussion 1329–1330.
6. Sosa CG, Althabe F, Belizan JM, et al. Bed rest in singleton preg-
nancies for preventing preterm birth. Cochrane Database Syst
Rev. 2015;CD003581.
7. Kovacevich GJ, Gaich SA, Lavin JP, et al. The prevalence of
thromboembolic events among women with extended bed rest
prescribed as part of the treatment for premature labor or preterm
premature rupture of membranes. Am J Obstet Gynecol. 2000;182:
1089–1092.
8. Kaji T, Yasui T, Suto M, et al. Effect of bed rest during pregnancy
on bone turnover markers in pregnant and postpartum women.
Bone. 2007;40:1088–1094.
9. Maloni JA. Antepartum bed rest for pregnancy complications:
efficacy and safety for preventing preterm birth. Biol Res Nurs.
2010;12:106–124.
10. Haas DM, Morgan AM, Deans SJ, et al. Ethanol for preventing
preterm birth in threatened preterm labor. Cochrane Database
Syst Rev. 2015;CD011445.
11. American College of Obstetricians and Gynecologists' Commit-
tee on Practice B-O. Practice Bulletin No. 171: Management of
Preterm Labor. Obstet Gynecol. 2016;128:e155–e164.
12. Reinebrant HE, Pileggi-Castro C, Romero CL, et al. Cyclo-
oxygenase (COX) inhibitors for treating preterm labour. Cochrane
Database Syst Rev. 2015;CD001992.
13. Niebyl JR, Blake DA, White RD, et al. The inhibition of prema-
ture labor with indomethacin. Am J Obstet Gynecol. 1980;136:
1014–1019.
14. Panter KR, Hannah ME, Amankwah KS, et al. The effect of indo-
methacin tocolysis in preterm labour on perinatal outcome: a
randomised placebo-controlled trial. Br J Obstet Gynaecol.
1999;106:467–473.
 Tocolysis: A Review of the Literature • CME Review Article
15. Zuckerman H, Shalev E, Gilad G, et al. Further study of the inhibi-
tion of premature labor by indomethacin. Part II double-blind
study. J Perinat Med. 1984;12:25–29.
16. Kurki T, Eronen M, Lumme R, et al. A randomized double-dummy
comparison between indomethacin and nylidrin in threatened
preterm labor. Obstet Gynecol. 1991;78:1093–1097.
17. Vermillion ST, Scardo JA, Lashus AG, et al. The effect of indometh-
acin tocolysis on fetal ductus arteriosus constriction with advanc-
ing gestational age. Am J Obstet Gynecol. 1997;177:256–259.
discussion 259–261.
18. Savage AH, Anderson BL, Simhan HN. The safety of prolonged
indomethacin therapy. Am J Perinatol. 2007;24:207–213.
19. Sandruck JC, Grobman WA, Gerber SE. The effect of short-term
indomethacin therapy on amniotic fluid volume. Am J Obstet
Gynecol. 2005;192:1443–1445.
20. Loe SM, Sanchez-Ramos L, Kaunitz AM. Assessing the neonatal
safety of indomethacin tocolysis: a systematic review with meta-
analysis. Obstet Gynecol. 2005;106:173–179.
21. Macones GA, Robinson CA. Is there justification for using indo-
methacin in preterm labor? An analysis of neonatal risks and ben-
efits. Am J Obstet Gynecol. 1997;177:819–824.
22. Norton ME, Merrill J, Kuller JA, et al. Neonatal complications after
the administration of indomethacin for preterm labor. N Engl J
Med. 1993;329:1602–1607.
23. Conde-Agudelo A, Romero R, Kusanovic JP. Nifedipine in the
management of preterm labor: a systematic review and meta-
analysis. Am J Obstet Gynecol. 2011;204:134.e1–134.e20.
24. Flenady V, Wojcieszek AM, Papatsonis DN, et al. Calcium chan-
nel blockers for inhibiting preterm labour and birth. Cochrane
Database Syst Rev. 2014;CD002255.
25. Arrowsmith S, Kendrick A, Wray S. Drugs acting on the pregnant
uterus. Obstet Gynaecol Reprod Med. 2010;20:241–247.
26. Crowther CA, Brown J, McKinlay CJ, et al. Magnesium sulphate
for preventing preterm birth in threatened preterm labour. Cochrane
Database Syst Rev. 2014;CD001060.
27. Mercer BM, Merlino AA, Society for Maternal-Fetal M. Magne-
sium sulfate for preterm labor and preterm birth. Obstet Gynecol.
2009;114:650–668.
Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
55
28. Magee LA, Miremadi S, Li J, et al. Therapy with both magnesium
sulfate and nifedipine does not increase the risk of serious
magnesium-related maternal side effects in women with pre-
eclampsia. Am J Obstet Gynecol. 2005;193:153–163.
29. Neilson JP, West HM, Dowswell T. Betamimetics for inhibiting
preterm labour. Cochrane Database Syst Rev. 2014;CD004352.
30. U.S. Food and Drug Administration. FDA Drug Safety Communi-
cation: new warnings against use of terbutaline to treat preterm
labor. Available at: https://www.fda.gov/Drugs/DrugSafety/
ucm243539.htm.
31. Haas DM, Caldwell DM, Kirkpatrick P, et al. Tocolytic therapy for
preterm delivery: systematic review and network meta-analysis.
BMJ. 2012;345:e6226.
32. Klauser CK, Briery CM, Martin RW, et al. A comparison of three
tocolytics for preterm labor: a randomized clinical trial. J Matern
Fetal Neonatal Med. 2014;27:801–806.
33. Manuck TA, Herrera CA, Korgenski EK, et al. Tocolysis for
women with early spontaneous preterm labor and advanced cer-
vical dilation. Obstet Gynecol. 2015;126:954–961.
34. Klauser CK, Briery CM, Tucker AR, et al. Tocolysis in women
with advanced preterm labor: a secondary analysis of a randomized
clinical trial. J Matern Fetal Neonatal Med. 2016;29:696–700.
35. Committee on Practice Bulletins-Obstetrics. ACOG Practice Bul-
letin No. 188: Prelabor Rupture of Membranes. Obstet Gynecol.
2018;131:e1–e14.
36. Fox NS, Gelber SE, Kalish RB, et al. Contemporary practice pat-
terns and beliefs regarding tocolysis among U.S. maternal-fetal
medicine specialists. Obstet Gynecol. 2008;112:42–47.
37. Mackeen AD, Seibel-Seamon J, Muhammad J, et al. Tocolytics
for preterm premature rupture of membranes. Cochrane Database
Syst Rev. 2014;CD007062.
38. ACOG Practice Bulletin No. 160: Premature Rupture of Membranes.
Obstet Gynecol. 2016;139:e39–e51.
39. Gyetvai K, Hannah ME, Hodnett ED, et al. Tocolytics for preterm
labor: a systematic review. Obstet Gynecol. 1999;94:869–877.
40. Haas DM, Imperiale TF, Kirkpatrick PR, et al. Tocolytic ther-
apy: a meta-analysis and decision analysis. Obstet Gynecol.
2009;113:585–594.